Project Summary There is a high comorbidity between substance use disorders (SUDs) and post-traumatic stress disorder (PTSD). A consequence of this comorbidity is that exposure to cues associated with trauma in a patient with PTSD may trigger relapse of drug seeking, even after successful treatment or periods of abstinence. Thus, a major goal of treatment for both PTSD and substance use disorders is to weaken the ability of environmental cues to induce relapse. One way to do this is through extinction techniques, in which the relation between the cue and the drug, or the cue and the traumatic memory, is severed. A major challenge for purely behavioral approaches to substance abuse and PTSD is that successful treatment with extinction often does not persist and relapse occurs with time, changes in context, or exposure to stress. Work in our laboratories has focused on manipulating epigenetic mechanisms to make the learning that occurs during extinction persistent, resulting in long-term weakening of fear responses (in the case of animal approaches to PTSD) and long-term elimination of drug-seeking (in animal approaches to substance abuse). However, our work, and most of the work in the general field of the neuroscience of extinction, comes from preclinical studies of basic mechanisms of extinction within approaches to PTSD (such as fear conditioning) or addiction (such as drug self- administration) in isolation; comparatively little is known about how learned fear and drug seeking interact at behavioral and molecular levels. We have developed a novel model of the comorbidity between PTSD and addiction in rodents that combines behavioral approaches that are well characterized at behavioral, circuit, and molecular levels. In this model, rodents receive exposure to a battery of shocks in one context and are tested for drug-seeking behaviors in a second context. Our preliminary data show that this exposure to a single battery of shocks causes persistent changes (>30 days) in responsivity to a mild stressor and results in increased cue-induced reinstatement of drug-seeking after extensive extinction. Thus, this approach captures a persistent context-independent change in drug-seeking that is not captured in other stress-induced reinstatement procedures and provides a strong basis for investigating, at a basic level, how reward and aversive processes interact across long periods of time and, at a translational level, how a single traumatic experience results in persistent effects on relapse after successful treatment. The three specific aims outlined in this application are designed to (1) elucidate the persistent behavioral and molecular effects of an acute trauma, (2) evaluate the post-trauma effects of pharmacological manipulation of a specific histone deacetylase (HDAC3) in circuits involved in extinction of fear and drug-seeking, and (3) to evaluate the mechanisms through which HDAC3 manipulations alter relapse after trauma. Our focus on epigenetic mechanisms holds significant promise for understanding how persistent changes in behavior are established following trauma, and provides a novel therapeutic avenue.